title: CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia.
abstract: Familial hypomagnesemia is a rare human disorder caused by renal or intestinal magnesium (Mg(2+)) wasting, which may lead to symptoms of Mg(2+) depletion such as tetany, seizures, and cardiac arrhythmias. Our knowledge of the physiology of Mg(2+) (re)absorption, particularly the luminal uptake of Mg(2+) along the nephron, has benefitted from positional cloning approaches in families with Mg(2+) reabsorption disorders; however, basolateral Mg(2+) transport and its regulation are still poorly understood. Here, by using a candidate screening approach, we identified CNNM2 as a gene involved in renal Mg(2+) handling in patients of two unrelated families with unexplained dominant hypomagnesemia. In the kidney, CNNM2 was predominantly found along the basolateral membrane of distal tubular segments involved in Mg(2+) reabsorption. The basolateral localization of endogenous and recombinant CNNM2 was confirmed in epithelial kidney cell lines. Electrophysiological analysis showed that CNNM2 mediated Mg(2+)-sensitive Na(+) currents that were significantly diminished in mutant protein and were blocked by increased extracellular Mg(2+) concentrations. Our data support the findings of a recent genome-wide association study showing the CNNM2 locus to be associated with serum Mg(2+) concentrations. The mutations found in CNNM2, its observed sensitivity to extracellular Mg(2+), and its basolateral localization signify a critical role for CNNM2 in epithelial Mg(2+) transport.
authors.affiliation: Department of Pediatric Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marchel
authors.initials: M
authors.lastname: Stuiver
authors.forename: Sergio
authors.initials: S
authors.lastname: Lainez
authors.forename: Constanze
authors.initials: C
authors.lastname: Will
authors.forename: Sara
authors.initials: S
authors.lastname: Terryn
authors.forename: Dorothee
authors.initials: D
authors.lastname: Günzel
authors.forename: Huguette
authors.initials: H
authors.lastname: Debaix
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sommer
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kopplin
authors.forename: Julia
authors.initials: J
authors.lastname: Thumfart
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Kampik
authors.forename: Uwe
authors.initials: U
authors.lastname: Querfeld
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.forename: Vladimír
authors.initials: V
authors.lastname: Němec
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Joost G
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: René J
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Iwan C
authors.initials: IC
authors.lastname: Meij
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics*; D016213:Cyclins / Q000737:chemistry / Q000235:genetics*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008274:Magnesium / Q000378:metabolism* / Q000494:pharmacology; D008275:Magnesium Deficiency / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C558175:CNNM2 protein, human; D027682:Cation Transport Proteins; D016213:Cyclins; D008274:Magnesium